Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming

T cell exhaustion is a hallmark of cancer and persistent infections, marked by inhibitory receptor upregulation, diminished cytokine secretion, and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex), but the metabolic principles governing Tpex maintenance and the regulatory circuits that control their exhaustion remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics, and metabolomic analyses, we show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the functional exhaustion of T cells. At the molecular level, we find that mitochondrial dysfunction causes redox stress,…

• CC
  Cincinnati Children's Hospital Medical Center
• DF
  Deutsche Forschungsgemeinschaft

  Awards: SFB-TR 338/1, project number 452881907, 452881907, TR 124, VA882/2-1, SFB 1526, 492620490, VA882/3-2, SFB 1525, SFB 1583/1, project number 492620490, SFB 1526/1, project number 454193335, 210879364, SFB-TR 124/3, project number 210879364, 453989101, 454193335, SFB 1525/1, project number 453989101
• IZ
  Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg